Acne vulgaris is the most common skin disease in man and affects more than 80% of the population at various times. The etiology of acne is multifactorial, with excessive sebum secretion, hyperkeratinization and bacterial colonization playing key roles in its pathology.
The sebaceous gland is a holocrine gland which normally is found only in association with hair follicles (therefore the terminology pilosebaceous). The gland continuously forms the complex fatty mixture known as sebum, which finds passage up the hair follicle, through the production and eventual lysis of lipid-filled cells. The basal sebaceous cells, lining the edge of the gland, undergo division and create two daughter cells, one of which differentiates into a lipid-filled sebaceous cell. The lipid accumulation eventually results in lysis of the sebaceous cells. The liberated sebum is deposited onto the skin surface after migrating through the follicular (pilosebaceous) duct.
The pilosebaceous duct also plays a critical function in the development of acne. Obstruction of the pilosebaceous duct, caused by a hyperkeratinization and proliferation of the keratinocytes of the duct, may be the primary lesion in the development of acne (Lavker et al., 1981). Numerous studies have demonstrated that the entire pilosebaceous duct shows abnormal changes, which include an increased turnover of cells of the basal layer and the creation of an abnormal terminally differentiated stratum corneocyte, termed a "retention hyperkeratosis" (Knutson, 1974; Lavker and Leyden, 1979; Wolff et al., 1975).
The primary lesion of acne is the comedo. The open comedo (blackhead) consists of a firm mass of keratin and sebum which blocks and dilates the follicle pore. The upper portion of the blackhead is darkened by slow oxidative changes (not by dirt), and the lower portions are white. The closed comedo (whitehead), which is a collection of keratin and sebum with the follicular opening blocked, are potentially the starting point of deep inflammatory lesions.
It has been demonstrated that compounds which reduce sebum production reduce the severity of acne. Example of such compounds are 13-cis-retinoic acid, spironolactone and cyproterone acetate (Farrell et al., 1980; Hammerstein et al., 1975; Lyons et al., 1982; Weissman et al., 1985). It has also been shown that 13-cis-retinoic acid reduces the size of human sebaceous glands up to 90% (Landthaler et al., 1980). However, this compound can cause deleterious side effects such as hypervitaminosis A.
There are several standard in vitro and in vivo models known in the art for evaluating the anti-acne activity of compounds. For example, one in vitro model is the inhibition of the proliferation of cultured human sebaceous cells. (Shapiro et al., 1989, Vane et al., 1991).
The Syrian hamster ear provides a standard model for sebaceous gland activity which is predictive of the anti-acne activity of a compound. The ventral side of the earlobes of the Syrian hamster is richly endowed with sebaceous glands. These glands are large and are similar to human sebaceous glands since they have an infundibulum, a sebaceous duct, multiple lobules, and a pilary unit which enters from below the gland (Plewig and Luderschmidt, 1977). The turnover time is similar to that seen in man and the gland is androgen dependent. The Syrian hamster ear sebaceous gland is sensitive to 13-cis-retinoic acid (Plewig et al., 1981).
The rhino mouse model of antikeratinization is used as a standard model for comedolytic activity. In this mutant hairless mouse, the pilary canal widens, accumulates keratin, and is transformed into a keratin-filled utricle that resembles a human comedo. When retinoids which are active in this test are applied topically or given systemically, the utricle size decreases and returns to a near normal appearance resembling a normal pilosebaceous unit (Mezick et al., 1984). This model represents a method to determine antikeratinizing potency differences among biologically active agents and appears to be selective for retinoids which influence follicular keratinization and cell differentiation.